madman
Super Moderator
Erectile Dysfunction: From Pathophysiology to Clinical Assessment (2022)
Vincenzo Mirone, Ferdinando Fusco, Luigi Cirillo, and Luigi Napolitano
3.1 Penile Erection
Penile erection is a complex phenomenon characterized by the equilibrium of the neurological, vascular, hormonal, and muscular compartments [1]. In normal conditions, penile erection requires coordinated involvement of intact central and peripheral nervous systems, corpora cavernosa, and spongiosa, normal arterial blood supply, and venous drainage [2].
Generally, erection is associated with several psychological and physical changes: heightened sexual arousal, full testicular ascent and swelling, dilatation of the urethral bulb, an increase in glans and coronal size, cutaneous flush over the epigastrium, chest, and buttocks, nipple erection, tachycardia and elevation in blood pressure, hyperventilation, and generalized myotonia [3].
3.1.1 Anatomy
We can divide the penis into three parts: root (radix), body (shaft), and glans [4].
3.1.2 Innervation
The penis is characterized by autonomic (sympathetic and parasympathetic) and somatic (sensory and motor) innervation systems. The autonomic system regulates the neurovascular events occurring during erection and detumescence. The somatic system is responsible for sensation and the contraction of the bulbocavernosus and ischiocavernosus muscles.
3.1.3 Vasculature
The penis receives arterial supply from three sources originating by internal pudendal arteries: dorsal arteries of the penis, deep arteries of the penis, and bulbourethral artery [8].
3.1.4 Erectile Process
The erectile process involves specifically the cavernous smooth musculature and the smooth muscles of the arteriolar and arterial walls [1].
3.2 Pathophysiology of Erectile Dysfunction
Erectile dysfunction (ED) is defined as the persistent inability to attain and/or maintain penile erection sufficient to permit satisfactory sexual performance [15]
Erectile dysfunction may affect physical and physiological health and has a strong impact on quality of life and relationships. It is recognized as a possible early sign of coronary artery and peripheral vascular disease. Therefore, physicians should ask male patients about sexual health in order to identify potential life-threatening underlying conditions such as cardiovascular disease [16, 17]. ED is known to have psychological as well as organic causes. Nonorganic erectile dysfunction is also known as psychogenic or adrenaline-mediated erectile dysfunction (noradrenaline-mediated or sympathetic-mediated erectile dysfunction). It has not been well studied but is an important factor to consider when evaluating and managing men with this condition [18].
Stress, depression, and anxiety are generally defined as heightened anxiety related to the inability to achieve and maintain an erection before or during sexual relations and are commonly associated with psychogenic erectile dysfunction [19].
Erectile dysfunction possibly generates by any process that impairs either the neural or the vascular pathways that contribute to an erection. Neurogenic erectile dysfunction is caused by a deficit in nerve signaling to the corpora cavernosa [20]. Such deficits can be secondary to, for example, spinal cord injury, multiple sclerosis, Parkinson’s disease, lumbar disc disease, traumatic brain injury, radical pelvic surgery (radical prostatectomy, radical cystectomy, and abdominoperineal resection), and diabetes. Upper motor neuron lesions (above spinal nerve T10) do not result in local changes in the penis but can inhibit the central nervous system (CNS)-mediated control of the erection. By contrast, sacral lesions (S2–S4 are typically responsible for reflexogenic erections) cause functional and structural alterations owing to decreased innervation [21].
The functional change resulting from such injuries is the reduction in NO load that is available to the smooth muscle. The structural changes center on apoptosis of the smooth muscle and endothelial cells of the blood vessels, as well as upregulation of fbrogenetic cytokines that lead to collagenization of the smooth muscle. These changes result in veno-occlusive dysfunction (venous leak). Vascular disease and endothelial dysfunction lead to erectile dysfunction through reduced blood inflow, arterial insufficiency, or arterial stenosis. Vasculogenic erectile dysfunction is by far the most common etiology of organic erectile dysfunction [22]. Many men assume that erectile dysfunction is a natural consequence of aging. But, despite age standing as an independent risk factor for ED, about one-third of 70-year-old men report no erectile difficulties. Thus, physicians should not automatically assume that erectile dysfunction is anyway attributable to aging.
Risk factors for developing erectile dysfunction include tobacco use, obesity, a sedentary lifestyle, and chronic alcohol use. These factors are believed to make hormonal changes that could easily lead to lower testosterone levels and result in impaired endothelial function [23–25].
Several studies have suggested that chronic inflammation and circulating inflammatory markers affect systemic endothelial function [26]. Chronic inflammation may, therefore, represent a link between ED and cardiovascular diseases (CVD). ED onset and severity are associated with increased expression of markers of inflammation. Markers and mediators such as C-reactive protein (CRP), intercellular adhesion molecule 1, interleukin (IL)-6, IL-10, and IL-1B, and tumor necrosis factor-alpha (TNF-α) were found to be expressed at higher levels in patients with ED. In addition, endothelial and prothrombotic factors such as von Willebrand factor (vWF), tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), and fibrinogen are also expressed at higher levels in ED patients [27, 28]. Androgens play an important role in both penile and vascular health, with cellular targets located in both endothelial and smooth muscle cells [29–32].
Androgens promote endothelial cell survival, inhibit proliferation and intimal migration of vascular smooth muscle cells, and reduce endothelial expression of pro-inflammatory markers [33]. Within the penis, low androgen levels are associated with apoptosis of endothelial and smooth muscle cells as well as with pathologic structural remodeling [34]. Besides, both hypo- and hyperthyroidism can lead to erectile impairment. Also, people diagnosed with hypertension, Mellitus diabetes, dyslipidemia, and depression have an increased risk of developing erectile dysfunction. The metabolic syndrome also known as syndrome X and insulin resistance syndrome is the term that consists of a cluster of disease states abdominal obesity, atherogenic dyslipidemia, raised blood pressure, insulin resistance ± glucose intolerance, pro-inflammatory state, and prothrombotic state. Coronary artery diseases and ED share similar risk factors such as hypertension, diabetes mellitus, smoking, and hypercholesterolemia, and many of these factors are part of MetS [35].
MetS may cause ED through multiple mechanisms. All components of MetS are frequently found in the obese population. Abdominal obesity promotes insulin resistance that is associated with hyperinsulinemia and hyperglycemia [36]. It may also lead to an abnormal lipid profile, hypertension, and vascular inflammation, all of which promote the development of atherosclerosis. Endothelial dysfunction leads to a decrease in vascular nitric oxide levels, with resulting impaired vasodilation; the increase in free radical concentration also leads to atherosclerotic damage. In light of these common pathways, MetS could be a strong risk factor for ED as well as ED might be a harbinger of cardiovascular diseases [18, 37]. Some drugs and medicines, for example, α-blockers, benzodiazepines, β-blockers, clonidine, digoxin, histamine H2-receptor blockers, ketoconazole, methyldopa, monoamine oxidase inhibitors, phenobarbital, phenytoin, selective serotonin reuptake inhibitors, spironolactone, thiazide diuretics, and tricyclic antidepressants can cause erectile dysfunction although the exact mechanisms are not always known [15]. The most common iatrogenic cause of erectile dysfunction is radical pelvic surgery [22]. Generally, the damage that occurs during these procedures is primarily neurogenic in nature (cavernous nerve injury) but accessory pudendal artery injury can also contribute. Pelvic fractures can also cause erectile dysfunction in a similar manner, owing to nerve distraction injury and arterial trauma [22]. Finally, patients with erectile dysfunction are more likely to also have premature ejaculation, lower urinary tract symptoms associated with benign prostatic hypertrophy (BPH), and overactive bladder compared with the general male population [38].
3.3 Diagnosis
The basic workup of a male patient seeking medical care for erectile dysfunction needs to include an evaluation of all the risk factors mentioned. Physicians should investigate the medical and sexual history and physically examine the lower genitourinary tract, the penis, and the testicles. Then, hormonal blood levels should be examined (i.e., testosterone, prolactin, LH, and FSH).
Vincenzo Mirone, Ferdinando Fusco, Luigi Cirillo, and Luigi Napolitano
3.1 Penile Erection
Penile erection is a complex phenomenon characterized by the equilibrium of the neurological, vascular, hormonal, and muscular compartments [1]. In normal conditions, penile erection requires coordinated involvement of intact central and peripheral nervous systems, corpora cavernosa, and spongiosa, normal arterial blood supply, and venous drainage [2].
Generally, erection is associated with several psychological and physical changes: heightened sexual arousal, full testicular ascent and swelling, dilatation of the urethral bulb, an increase in glans and coronal size, cutaneous flush over the epigastrium, chest, and buttocks, nipple erection, tachycardia and elevation in blood pressure, hyperventilation, and generalized myotonia [3].
3.1.1 Anatomy
We can divide the penis into three parts: root (radix), body (shaft), and glans [4].
3.1.2 Innervation
The penis is characterized by autonomic (sympathetic and parasympathetic) and somatic (sensory and motor) innervation systems. The autonomic system regulates the neurovascular events occurring during erection and detumescence. The somatic system is responsible for sensation and the contraction of the bulbocavernosus and ischiocavernosus muscles.
3.1.3 Vasculature
The penis receives arterial supply from three sources originating by internal pudendal arteries: dorsal arteries of the penis, deep arteries of the penis, and bulbourethral artery [8].
3.1.4 Erectile Process
The erectile process involves specifically the cavernous smooth musculature and the smooth muscles of the arteriolar and arterial walls [1].
3.2 Pathophysiology of Erectile Dysfunction
Erectile dysfunction (ED) is defined as the persistent inability to attain and/or maintain penile erection sufficient to permit satisfactory sexual performance [15]
Erectile dysfunction may affect physical and physiological health and has a strong impact on quality of life and relationships. It is recognized as a possible early sign of coronary artery and peripheral vascular disease. Therefore, physicians should ask male patients about sexual health in order to identify potential life-threatening underlying conditions such as cardiovascular disease [16, 17]. ED is known to have psychological as well as organic causes. Nonorganic erectile dysfunction is also known as psychogenic or adrenaline-mediated erectile dysfunction (noradrenaline-mediated or sympathetic-mediated erectile dysfunction). It has not been well studied but is an important factor to consider when evaluating and managing men with this condition [18].
Stress, depression, and anxiety are generally defined as heightened anxiety related to the inability to achieve and maintain an erection before or during sexual relations and are commonly associated with psychogenic erectile dysfunction [19].
Erectile dysfunction possibly generates by any process that impairs either the neural or the vascular pathways that contribute to an erection. Neurogenic erectile dysfunction is caused by a deficit in nerve signaling to the corpora cavernosa [20]. Such deficits can be secondary to, for example, spinal cord injury, multiple sclerosis, Parkinson’s disease, lumbar disc disease, traumatic brain injury, radical pelvic surgery (radical prostatectomy, radical cystectomy, and abdominoperineal resection), and diabetes. Upper motor neuron lesions (above spinal nerve T10) do not result in local changes in the penis but can inhibit the central nervous system (CNS)-mediated control of the erection. By contrast, sacral lesions (S2–S4 are typically responsible for reflexogenic erections) cause functional and structural alterations owing to decreased innervation [21].
The functional change resulting from such injuries is the reduction in NO load that is available to the smooth muscle. The structural changes center on apoptosis of the smooth muscle and endothelial cells of the blood vessels, as well as upregulation of fbrogenetic cytokines that lead to collagenization of the smooth muscle. These changes result in veno-occlusive dysfunction (venous leak). Vascular disease and endothelial dysfunction lead to erectile dysfunction through reduced blood inflow, arterial insufficiency, or arterial stenosis. Vasculogenic erectile dysfunction is by far the most common etiology of organic erectile dysfunction [22]. Many men assume that erectile dysfunction is a natural consequence of aging. But, despite age standing as an independent risk factor for ED, about one-third of 70-year-old men report no erectile difficulties. Thus, physicians should not automatically assume that erectile dysfunction is anyway attributable to aging.
Risk factors for developing erectile dysfunction include tobacco use, obesity, a sedentary lifestyle, and chronic alcohol use. These factors are believed to make hormonal changes that could easily lead to lower testosterone levels and result in impaired endothelial function [23–25].
Several studies have suggested that chronic inflammation and circulating inflammatory markers affect systemic endothelial function [26]. Chronic inflammation may, therefore, represent a link between ED and cardiovascular diseases (CVD). ED onset and severity are associated with increased expression of markers of inflammation. Markers and mediators such as C-reactive protein (CRP), intercellular adhesion molecule 1, interleukin (IL)-6, IL-10, and IL-1B, and tumor necrosis factor-alpha (TNF-α) were found to be expressed at higher levels in patients with ED. In addition, endothelial and prothrombotic factors such as von Willebrand factor (vWF), tissue plasminogen activator (tPA), plasminogen activator inhibitor 1 (PAI-1), and fibrinogen are also expressed at higher levels in ED patients [27, 28]. Androgens play an important role in both penile and vascular health, with cellular targets located in both endothelial and smooth muscle cells [29–32].
Androgens promote endothelial cell survival, inhibit proliferation and intimal migration of vascular smooth muscle cells, and reduce endothelial expression of pro-inflammatory markers [33]. Within the penis, low androgen levels are associated with apoptosis of endothelial and smooth muscle cells as well as with pathologic structural remodeling [34]. Besides, both hypo- and hyperthyroidism can lead to erectile impairment. Also, people diagnosed with hypertension, Mellitus diabetes, dyslipidemia, and depression have an increased risk of developing erectile dysfunction. The metabolic syndrome also known as syndrome X and insulin resistance syndrome is the term that consists of a cluster of disease states abdominal obesity, atherogenic dyslipidemia, raised blood pressure, insulin resistance ± glucose intolerance, pro-inflammatory state, and prothrombotic state. Coronary artery diseases and ED share similar risk factors such as hypertension, diabetes mellitus, smoking, and hypercholesterolemia, and many of these factors are part of MetS [35].
MetS may cause ED through multiple mechanisms. All components of MetS are frequently found in the obese population. Abdominal obesity promotes insulin resistance that is associated with hyperinsulinemia and hyperglycemia [36]. It may also lead to an abnormal lipid profile, hypertension, and vascular inflammation, all of which promote the development of atherosclerosis. Endothelial dysfunction leads to a decrease in vascular nitric oxide levels, with resulting impaired vasodilation; the increase in free radical concentration also leads to atherosclerotic damage. In light of these common pathways, MetS could be a strong risk factor for ED as well as ED might be a harbinger of cardiovascular diseases [18, 37]. Some drugs and medicines, for example, α-blockers, benzodiazepines, β-blockers, clonidine, digoxin, histamine H2-receptor blockers, ketoconazole, methyldopa, monoamine oxidase inhibitors, phenobarbital, phenytoin, selective serotonin reuptake inhibitors, spironolactone, thiazide diuretics, and tricyclic antidepressants can cause erectile dysfunction although the exact mechanisms are not always known [15]. The most common iatrogenic cause of erectile dysfunction is radical pelvic surgery [22]. Generally, the damage that occurs during these procedures is primarily neurogenic in nature (cavernous nerve injury) but accessory pudendal artery injury can also contribute. Pelvic fractures can also cause erectile dysfunction in a similar manner, owing to nerve distraction injury and arterial trauma [22]. Finally, patients with erectile dysfunction are more likely to also have premature ejaculation, lower urinary tract symptoms associated with benign prostatic hypertrophy (BPH), and overactive bladder compared with the general male population [38].
3.3 Diagnosis
The basic workup of a male patient seeking medical care for erectile dysfunction needs to include an evaluation of all the risk factors mentioned. Physicians should investigate the medical and sexual history and physically examine the lower genitourinary tract, the penis, and the testicles. Then, hormonal blood levels should be examined (i.e., testosterone, prolactin, LH, and FSH).
